BACKGROUND: Somatoform disorders are characterised by chronic, medically unexplained physical symptoms (MUPS). Although different medications are part of treatment routines for people with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications. We aimed to synthesise to improve optimal treatment decisions.OBJECTIVES: To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults.SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 17 January 2014). This register includes relevant randomised controlled trials (RCTs) from The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). To identify ongoing trials, we searched ClinicalTrials.gov, Current Controlled Trials metaRegister, the World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry. For grey literature, we searched ProQuest Dissertation {\&} Theses Database, OpenGrey, and BIOSIS Previews. We handsearched conference proceedings and reference lists of potentially relevant papers and systematic reviews and contacted experts in the field.SELECTION CRITERIA: We selected RCTs or cluster RCTs of pharmacological interventions versus placebo, treatment as usual, another medication, or a combination of different medications for somatoform disorders in adults. We included people fulfilling standardised diagnostic criteria for somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, or somatoform pain disorder.DATA COLLECTION AND ANALYSIS: One review author and one research assistant independently extracted data and assessed risk of bias. Primary outcomes included the severity of MUPS on a continuous measure, and acceptability of treatment.MAIN RESULTS: We included 26 RCTs (33 reports), with 2159 participants, in the review. They examined the efficacy of different types of antidepressants, the combination of an antidepressant and an antipsychotic, antipsychotics alone, or natural products (NPs). The duration of the studies ranged between two and 12 weeks.One meta-analysis of placebo-controlled studies showed no clear evidence of a significant difference between tricyclic antidepressants (TCAs) and placebo for the outcome severity of MUPS (SMD -0.13; 95{\%} CI -0.39 to 0.13; 2 studies, 239 participants; I(2) = 2{\%}; low-quality evidence). For new-generation antidepressants (NGAs), there was very low-quality evidence showing they were effective in reducing the severity of MUPS (SMD -0.91; 95{\%} CI -1.36 to -0.46; 3 studies, 243 participants; I(2) = 63{\%}). For NPs there was low-quality evidence that they were effective in reducing the severity of MUPS (SMD -0.74; 95{\%} CI -0.97 to -0.51; 2 studies, 322 participants; I(2) = 0{\%}).One meta-analysis showed no clear evidence of a difference between TCAs and NGAs for severity of MUPS (SMD -0.16; 95{\%} CI -0.55 to 0.23; 3 studies, 177 participants; I(2) = 42{\%}; low-quality evidence). There was also no difference between NGAs and other NGAs for severity of MUPS (SMD -0.16; 95{\%} CI -0.45 to 0.14; 4 studies, 182 participants; I(2) = 0{\%}).Finally, one meta-analysis comparing selective serotonin reuptake inhibitors (SSRIs) with a combination of SSRIs and antipsychotics showed low-quality evidence in favour of combined treatment for severity of MUPS (SMD 0.77; 95{\%} CI 0.32 to 1.22; 2 studies, 107 participants; I(2) = 23{\%}).Differences regarding the acceptability of the treatment (rate of all-cause drop-outs) were neither found between NGAs and placebo (RR 1.01, 95{\%} CI 0.64 to 1.61; 2 studies, 163 participants; I(2) = 0{\%}; low-quality evidence) or NPs and placebo (RR 0.85, 95{\%} CI 0.40 to 1.78; 3 studies, 506 participants; I(2) = 0{\%}; low-quality evidence); nor between TCAs and other medication (RR 1.48, 95{\%} CI 0.59 to 3.72; 8 studies, 556 participants; I(2) =14{\%}; low-quality evidence); nor between antidepressants and the combination of an antidepressant and an antipsychotic (RR 0.80, 95{\%} CI 0.25 to 2.52; 2 studies, 118 participants; I(2) = 0{\%}; low-quality evidence). Percental attrition rates due to adverse effects were high in all antidepressant treatments (0{\%} to 32{\%}), but low for NPs (0{\%} to 1.7{\%}).The risk of bias was high in many domains across studies. Seventeen trials (65.4{\%}) gave no information about random sequence generation and only two (7.7{\%}) provided information about allocation concealment. Eighteen studies (69.2{\%}) revealed a high or unclear risk in blinding participants and study personnel; 23 studies had high risk of bias relating to blinding assessors. For the comparison NGA versus placebo, there was relatively high imprecision and heterogeneity due to one outlier study. Although we identified 26 studies, each comparison only contained a few studies and small numbers of participants so the results were imprecise.AUTHORS' CONCLUSIONS: The current review found very low-quality evidence for NGAs and low-quality evidence for NPs being effective in treating somatoform symptoms in adults when compared with placebo. There was some evidence that different classes of antidepressants did not differ in efficacy; however, this was limited and of low to very low quality. These results had serious shortcomings such as the high risk of bias, strong heterogeneity in the data, and small sample sizes. Furthermore, the significant effects of antidepressant treatment have to be balanced against the relatively high rates of adverse effects. Adverse effects produced by medication can have amplifying effects on symptom perceptions, particularly in people focusing on somatic symptoms without medical causes. We can only draw conclusions about short-term efficacy of the pharmacological interventions because no trial included follow-up assessments. For each of the comparisons where there were available data on acceptability rates (NGAs versus placebo, NPs versus placebo, TCAs versus other medication, and antidepressants versus a combination of an antidepressant and an antipsychotic), no clear differences between the intervention and comparator were found.Future high-quality research should be carried out to determine the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly, and to follow-up participants over longer periods (the longest follow up was just 12 weeks). Another idea for future research would be to include other outcomes such as functional impairment or dysfunctional behaviours and cognitions as well as the classical outcomes such as symptom severity, depression, or anxiety.

Pharmacological interventions for somatoform disorders in adults.

In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

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From inflammation to sickness and depression: when the immune system subjugates the brain

The detection of psychiatric illness by questionnaire

Because depression and painful symptoms commonly occur together, we conducted a literature review to determine the prevalence of both conditions and the effects of comorbidity on diagnosis, clinical outcomes, and treatment. The prevalences of pain in depressed cohorts and depression in pain cohorts are higher than when these conditions are individually examined. The presence of pain negatively affects the recognition and treatment of depression. When pain is moderate to severe, impairs function, and/or is refractory to treatment, it is associated with more depressive symptoms and worse depression outcomes (eg, lower quality of life, decreased work function, and increased health care utilization). Similarly, depression in patients with pain is associated with more pain complaints and greater impairment. Depression and pain share biological pathways and neurotransmitters, which has implications for the treatment of both concurrently. A model that incorporates assessment and treatment of depression and pain simultaneously is necessary for improved outcomes.

https://jamanetwork.com/journals/jamainternalmedicine/articlepdf/216320/ira30040_2433_2445.pdf

Depression and pain comorbidity: a literature review.

STUDY DESIGN: The literature on psychological factors in neck and back pain was systematically searched and reviewed.

OBJECTIVES: To summarize current knowledge concerning the role of psychological variables in the etiology and development of neck and back pain.

SUMMARY OF BACKGROUND DATA: Recent conceptions of spinal pain, especially chronic back pain, have highlighted the role of psychological factors. Numerous studies subsequently have examined the effects of various psychological factors in neck and back pain. There is a need to review this material to ascertain what conclusions may be drawn.

METHODS: Medical and psychological databases and cross-referencing were used to locate 913 potentially relevant articles. A table of 37 studies was constructed, consisting only of studies with prospective designs to ensure quality. Each study was reviewed for the population studied, the psychological predictor variables, and the outcome.

RESULTS: The available literature indicated a clear link between psychological variables and neck and back pain. The prospective studies indicated that psychological variables were related to the onset of pain, and to acute, subacute, and chronic pain. Stress, distress, or anxiety as well as mood and emotions, cognitive functioning, and pain behavior all were found to be significant factors. Personality factors produced mixed results. Although the level of evidence was low, abuse also was found to be a potentially significant factor.

CONCLUSIONS: Psychological factors play a significant role not only in chronic pain, but also in the etiology of acute pain, particularly in the transition to chronic problems. Specific types of psychological variables emerge and may be important in distinct developmental time frames, also implying that assessment and intervention need to reflect these variables. Still, psychological factors account for only a portion of the variance, thereby highlighting the multidimensional view. Because the methodologic quality of the studies varied considerably, future research should focus on improving quality and addressing new questions such as the mechanism, the developmental time factor, and the relevance that these risk factors have for intervention.

A review of psychological risk factors in back and neck pain.

Six-hundred-seven employees in 3 metal industry plants were studied for depressive and distress symptoms, musculoskeletal symptoms, and findings in the musculo-skeletal system made by a physiotherapist. Measurements were made 3 times at 5-year intervals. The mean distress and depressive symptom scores of the first 2 examinations predicted the change in several musculo-skeletal symptom measures during the second 5-year period, when the effects of age and occupational class were accounted for in multiple regression analysis. They also predicted the development in clinical musculoskeletal findings in men. The proportions of variance explained by the depressive and distress symptoms were modest in magnitude. Analogous analyses were made with reference to the reverse temporal sequence: musculoskeletal disorders were considered as predating the development in depressive and distress symptoms. The musculoskeletal symptom scores were associated with the change in the stress symptoms in men, as did the clinical findings in the neck-shoulder and low back regions. None of the musculoskeletal morbidity scores predicted the change in the depressive symptoms in either sex. We conclude that depressive symptoms predict future musculoskeletal disorders, but not vice versa, whereas the association of stress symptoms and musculoskeletal disorders is reciprocal.

Depressive and distress symptoms as predictors of low back pain, neck-shoulder pain, and other musculoskeletal morbidity: a 10-year follow-up of metal industry employees

In the last 30 years antidepressant drugs have been used increasingly in the treatment of patients with chronic pain. This article reviews the results of some 40 placebo-controlled studies. It is difficult to make comparisons between the various studies because they often differ in terms of pain conditions, patient selection, antidepressant drug used, dosages, trial design, etc. However, in spite of this heterogeneity and other methodological problems it is clear that a wide range of pain conditions are responsive to antidepressant drug treatment, in particular: headache, migraine, facial pain, neurogenic pain, fibrositis, and probably arthritis and rheumatoid arthritis. More data need to be gathered in cancer pain, and in other conditions such as low back pain for which no, or very limited, effect has been shown. The beneficial effects of antidepressant drugs is in most cases of a mild to moderate degree, some time lag is necessary before it is completely manifest, and it tends to persist over time if drug treatment is continued in the long term. Strong evidence of efficacy is not evident for all the antidepressants, and there are probably significant differences in this respect between various drugs. The effect of a drug on pain does not seem necessarily to be related to its effect on mood. Further studies are needed to clarify this topic, and it will be necessary to examine specific pain conditions, compare different antidepressants, with reference to each other and to placebo, further investigate the role of drug plasma concentrations and control for the presence of concomitant psychiatric disturbances and for organic lesions responsible for the pain symptomatology.

The use of antidepressants in the treatment of chronic pain. A review of the current evidence.

The authors evaluated the correlation between depressive symptoms and the onset of physical illness in a population of blue-collar workers in a metallurgic and machine factory in the region of Venice.

Depression and Physical Illness

• Ninety-nine of 118 patients receiving cardiac valve replacements (n = 55) or coronary artery bypass grafts (n = 44) were studied before surgery and again one year after surgery. Psychological, social, and physical variables were assessed. For the 19 subjects not returning for follow-up, medical data collected by their general practitioner were available. The physical results of surgery were good, with over 90% of the patients showing improvement. Mean scores for psychological distress and quality of life improved; however, a bad psychosocial adjustment was present in about 25% of patients at follow-up. Bad psychosocial adjustment was not correlated with surgical results. The preoperative variables most predictive of poor psychosocial outcome were high scores in the general hypochondriasis and irritability subscales of the Illness Behaviour Questionnaire, bad psychological adjustment characterized by high anxiety, depression, and global scores on the Symptom Distress Checklist, and ischemic rather than valvular heart disease. ( Arch Intern Med 1987;147:473-477)

Psychosocial outcome one year after heart surgery. A prospective study.

The frequencies of DSM-III diagnoses in 30 patients with dyspepsia of unknown origin and 20 patients with organic dyspepsia were compared. Dyspepsia of unknown origin was associated with a higher prevalence of psychiatric diagnoses (86.7% versus 25.0%), particularly anxiety disturbances (66.7%).

Guido Magni

Papers

Depressive and distress symptoms as predictors of low back pain, neck-shoulder pain, and other musculoskeletal morbidity: a 10-year follow-up of metal industry employees

The use of antidepressants in the treatment of chronic pain. A review of the current evidence.

Depression and Physical Illness

Psychosocial outcome one year after heart surgery. A prospective study.

DSM-III diagnoses associated with dyspepsia of unknown cause.